Abstract This is a renewal of NIH grant DK031036, the original grant to the Kahn lab, which is now in its 38th year and was granted MERIT status at the last renewal. Since inception, this grant has focused on the insulin and IGF-1 receptors, their signaling pathways and their alterations in physiologic and pathologic states. Over the past decade, we have made tremendous progress in understanding the signaling and biological roles of these receptors through both in vitro and in vivo studies. These include extensive studies using gene targeting to create single and combinatorial knockouts of insulin and IGF-1 receptors (IR and IGF1R); combinatorial knockouts IR with post-receptors effectors of insulin action (IRS and FoxO proteins); and tissue-specific and inducible knockouts to determine the role of IR and IGF1R in individual tissues in normal physiology and the pathophysiology of diabetes. In addition, in vitro we have defined differential signaling by insulin and IGF-1 receptors, and unique actions of insulin and IGF-1 in different cell types. As a result, since the last competitive renewal, this grant has provided support for 88 published papers which have led to new insights into the complex nature of the insulin/IGF-1 signaling network, the contribution of insulin resistance in different organs to diabetes and metabolic syndrome, as well as evidence on how tissues communicate with one another in insulin resistant states. In addition, we have made novel observations regarding the role of insulin action in non-classical target tissues, like the brain, intestine, endothelial and iPS cells; the presence of novel insulin-like peptides in viruses, and potential for signaling by unoccupied IR and IGF1R. During the coming grant period, our aims are to continue to expand our understanding of insulin/IGF1 action by 1) defining the differential roles of the extra- and intra-cellular domains of IR and IGF1R in signaling in vitro and in vivo using three complementary strategies [mass spectroscopy based phosphoproteomic analysis of insulin/IGF-1 receptor mutants and chimeric receptors in vitro; creation of a new generation of knock-in mouse models in which IR is replaced by IGF1R, by chimeric insulin/IGF-1 receptors or by substitutions in the juxtamembrane domain of the receptor important in differences in IR vs IGF1R signaling, and use of newly discovered viral insulin-like peptides (VILPs) to explore differences in IR/IGF1R signaling]; 2) determine the nature of signaling by the unoccupied insulin and IGF-1 receptors involved in control of gene expression, autophagy and apoptosis and identify the domains of the receptors mediating these effects and the signaling proteins that interact with them and 3) continuing to define the role of insulin signaling in brain on astrocytes vs neurons using global and region-specific IR knockouts; insulin regulation of gene expression and metabolite levels in brain; and the interaction of insulin resistance in brain with genetic risks in pathogenesis of Alzheimer?s Disease. Together these studies will continue to help unravel new aspects in the mechanisms of insulin/IGF-1 receptor signaling and their alterations in diabetes, metabolic and neurodegenerative disease.